Causal association of micronutrients with osteonecrosis: evidence from a bidirectional Mendelian randomization trial
Li Wei1, Chai Jinlian2, Jia Haifeng3, Li Hanzheng3, Sun Tiefeng4, Liang Xuezhen3
1College of Traditional Chinese Medicine, 2College of Pharmacy, 3First College of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, Shandong Province, China; 4Shandong Provincial Research Institute of Traditional Chinese Medicine, Jinan 250014, Shandong Province, China
Abstract: BACKGROUND: Osteonecrosis is a common refractory disease in clinical practice, and observational studies have suggested that micronutrients may have a prognostic role in osteonecrosis. However, the specific causal association between micronutrients and osteonecrosis is not known.
OBJECTIVE: To explore the causal association between micronutrients and osteonecrosis by Mendelian randomization using summary data from a large population-based genome-wide association study (GWAS) for clinical diagnosis and treatment.
METHODS: The required exposure and outcome data (calcium, magnesium, iron, vitamin E, carotenoids, retinol & osteonecrosis) were extracted from the IEU OpenGWAS database, GWAS catalog database, and FinnGen database. Data were analyzed by bidirectional Mendelian randomization with inverse-variance weighted as the primary study method, and weighted median method, simple mode method, weighted mode method, and MR-Egger regression to complement the results. The reliability of the data was then verified through sensitivity analyses.
RESULTS AND CONCLUSION: (1) The results found a positive correlation between serum iron concentration and osteonecrosis, while no correlation was found for other micronutrients. There was no reverse causality in all the data. (2) The results of sensitivity analysis showed a robust causality. (3) By Mendelian randomization method, this study provided evidence of causality between serum iron concentration and osteonecrosis, and understanding the causality of micronutrient elements on osteonecrosis can help in the clinical diagnosis and treatment of osteonecrosis, which is of great clinical significance.
Key words: osteonecrosis, micronutrients, Mendelian randomization, causality, reverse causality, genome-wide association study, ferroptosis, instrumental variable